Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for RRMS (RAM-MS)

NCT03477500 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: 2017-001362-25
• Study Type: interventional
• Target: 100
• Locations: 4 countries
• Sites: 8

Brief Summary

This study is a randomized multicentre, multinational, treatment interventional study of RRMS patients with breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication. The study has two treatment arms; arm A: HSCT (hematopoietic stem cell transplantation) and arm B: alemtuzumab, cladribine or ocrelizumab. A pre-planned 3-year follow-up extension period will be performed depending on future funding. The aim of the study is to assess the effectiveness and side effects of a new treatment intervention in RRMS; HSCT, and, thereby, the value of HSCT in clinical practice. Data from recently published patient series indicate that HSCT may have a significantly higher treatment effect than currently registered RRMS immunomodulatory treatments. This study will determine the relative role of HSCT versus alemtuzumab, cladribine or ocrelizumab.

Conditions

Multiple Sclerosis

Keywords

multiple sclerosis,; HSCT; alemtuzumab; RCT

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol).

  A protocol-defined disease activity event is the occurrence of at least one of the following: * A new T1 Gd-enhanced lesion on MRI of the brain and spinal cord * A new T2 hyperintense lesion on MRI of brain and spinal cord * A protocol-defined MS relapse (see below) * 24 week confirmed disability progression based on increases in Expanded Disability Status Scale (EDSS)

  2 year (96 week) period with a 5 year (240 week) planned extension

Secondary Outcomes (16)

• NEDA-4

  2 year (96 week) period

• Pre-planned study extension:

  5 year (240 week) period.

• Time to first protocol-defined disease activity event

  2 year (96 week) period, with planned extension for 5 year (240 week) period

• Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240

  2 year (96 week) period, with planned extension for 5 year (240 week) period

• The proportion of patients who, at Week 96, have protocol-defined Confirmed Disability Improvement (CDI) , confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline

  2 year (96 week) period, with planned extension for 5 year (240 week) period

Other Outcomes (7)

• Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores

  2 year (96 week) period, with planned extension for 5 year (240 week) period

• Overall survival rate

  2 year (96 week) period, with planned extension for 5 year (240 week) period

• Rate and nature of adverse events

  2 year (96 week) period, with planned extension for 5 year (240 week) period

Study Arms (2)

HSCT (Cyclophosphamide and ATG)

EXPERIMENTAL

Day 1: Cyclophosphamide 2.0 g/m2 body surface area Days 5-10: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight/day sc. Day 11 and until apheresis is discontinued: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight x 2 sc/day. HSCT days -5 to -2: Cyclophosphamide 50 mg/kg/day. HSCT days -5 to -1: Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5 mg/kg body weight iv on day -5, 1.0 mg ATG-rabbit/kg will be given iv on day -4, and 1.5 mg ATG-rabbit /kg will be given iv on days -3,-2 and -1 over 10 hours. HSCT day 0: Reinfusion of a minimum of 3,0 x 106 CD 34+ cells/kg body weight.

Drug: Cyclophosphamide and ATG

Alemtuzumab, Cladribine or Ocrelizumab

ACTIVE COMPARATOR

Alemtuzumab, Cladribine or Ocrelizumab administered after the label of the study drug.

Drug: Alemtuzumab; Drug: Cladribine Pill; Drug: Ocrelizumab

Interventions

Cyclophosphamide and ATG DRUG

Hematopoetic stem cell transplantation

Also known as: Sendoxan

HSCT (Cyclophosphamide and ATG)

Alemtuzumab DRUG

Alemtuzumab (Lemtrada)

Also known as: Lemtrada

Alemtuzumab, Cladribine or Ocrelizumab

Cladribine Pill DRUG

Cladribine (Mavenclad)

Also known as: Mavenclad

Alemtuzumab, Cladribine or Ocrelizumab

Ocrelizumab DRUG

Ocrelizumab (Ocrevus)

Also known as: Ocrevus

Alemtuzumab, Cladribine or Ocrelizumab

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between ≥18 to ≤50, both genders
• Women of childbearing potential\* (WOCBP) and men in a sexual relation with WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.
• Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1
• An EDSS score of 0 to 5.5
• Significant inflammatory disease activity in the last year despite treatment with standard disease modifying therapy (interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, natalizumab)
• a. Significant inflammatory disease activity is defined by: i. One or more clinically reported multiple sclerosis (MS) relapse(s), ii. AND 1 or more T1 Gd-enhanced lesion(s), iii. OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) The relapse(s) must have been treated with iv or oral high dose corticosteroids prescribed by a neurologist, and must have occurred 3 or more months after the onset of an immunomodulatory treatment, as MS immunomodulatory treatment may reach full effect after 3 months or more2.
• The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden or possibly other European countries to an assigned study site.
• Signed informed consent and expected patient cooperation regarding the treatment schemes and procedures planned in the treatment and follow-up periods must be obtained and documented according to ICH GCP and national/local regulations.

You may not qualify if:

• Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids
• Any illness or prior treatment that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy or high-dose glucocorticosteroids
• Any ongoing infection, including Tbc, CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HIV or syphilis infections, as well as heaptitis B surface antigen positivity and/or hepatitis C PCR positivity verified at Visit 1
• Current or previous treatments with long-term effects that may influence the treatment effects or potential toxicities/side effects of the treatment arms. This includes, but is not restricted to previous treatment with rituximab, mitoxantrone, alemtuzumab, cladribin and ocrelizumab
• Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
• Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
• Prior or current major depression
• Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol.
• Prior or current alcohol or drug dependencies
• Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
• Significant hypertension: BP \> 180/110
• Active malignancy, or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
• Known untreated or unregulated thyroid disease
• Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
• WBC \< 1,5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC \< 1,5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be \> 1,5 x 109/L before start of study treatment.

Sponsors & Collaborators

• Haukeland University Hospital: lead

Study Sites (8)

Rigshospitalet

Copenhagen, Denmark

Location

VUmc

Amsterdam, Netherlands

Location

Haukeland University Hospital

Bergen, Norway

Location

Akershus University Hospital

Oslo, Norway

Location

University Hospital of North Norway

Tromsø, Norway

Location

St. Olav's University Hospital

Trondheim, Norway

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Akademiska sjukhuset

Uppsala, Sweden

Location

Related Links

• Study site (in Norwegian)

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Cyclophosphamide; Alemtuzumab; Cladribine; ocrelizumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Lars Bø, MD, Phd

  Haukeland University Hospital

  STUDY DIRECTOR

• Anne Kristine Lehmann, MD, PhD

  Haukeland University Hospital

  STUDY CHAIR

• Astrid Kittang, MD, PhD

  Haukeland University Hospital

  STUDY CHAIR

• Einar Kristoffersen, MD, PhD

  Haukeland University Hospital

  STUDY CHAIR

• Øivind Torkildsen, MD, PhD

  Haukeland University Hospital

  STUDY CHAIR

• Trygve Holmøy, MD, PhD

  University Hospital, Akershus

  PRINCIPAL INVESTIGATOR

• Margitta Kampman, MD, PhD

  Tromsø University Hospital

  PRINCIPAL INVESTIGATOR

• Kathrine K Liane, MD

  St. Olavs Hospital

  PRINCIPAL INVESTIGATOR

• Joachim Burman, MD, PhD

  Akademiska sjukhuset, Uppsala

  PRINCIPAL INVESTIGATOR

• Morten Blinkenberg, MD, PhD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• Jan Lycke, MD, PhD

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2018
• First Posted: March 26, 2018
• Study Start: March 21, 2018
• Primary Completion (Estimated): November 21, 2026
• Study Completion (Estimated): March 21, 2028
• Last Updated: June 25, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will be available within publication of the results.
• Access Criteria: Data access requests will be reviewed by the RAM-MS steering committee. Requestors will be required to sign a data access agreement.

Locations

SE (2); DK (1); NL (1); NO (4)